Gold(I)-catalyzed enantioselective carboalkoxylation of alkynes

Article abstract of DOI:10.1021/ja407150h

A highly enantioselective carboalkoxylation of alkynes catalyzed by cationic (DTBM-MeO-Biphep)gold(I) complexes is reported. Various optically active β-alkoxyindanone derivatives were obtained in good yields with high enantioselectivities. Furthermore, this methodology was extended to the enantioselective synthesis of 3-methoxycyclopentenones. The reaction is proposed to proceed through an enantioselective cyclization of intermediates containing vinylgold(I) and prochiral oxocarbenium moieties.

Full text of DOI:10.1021/ja407150h

Communication
pubs.acs.org/JACS
Gold(I)-Catalyzed Enantioselective Carboalkoxylation of Alkynes
Weiwei Zi and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Acetals are widely used protecting groups for aldehydes
ABSTRACT: A highly enantioselective carboalkoxylation
of alkynes catalyzed by cationic (DTBM-MeO-Biphep)-
gold(I) complexes is reported. Various optically active β-
alkoxyindanone derivatives were obtained in good yields
with high enantioselectivities. Furthermore, this method-
ology was extended to the enantioselective synthesis of 3-
methoxycyclopentenones. The reaction is proposed to
proceed through an enantioselective cyclization of
intermediates containing vinylgold(I) and prochiral
oxocarbenium moieties.
because of their chemical inertness under many reaction
conditions. Nevertheless, the use of transition-metal catalysts
affords the opportunity to use them as reactive functionalities.5
In 2004, Yamamoto reported the palladium- and platinum-
catalyzed carboalkoxylation of alkynes using acetals.1b,c Inspired
by their work, we reasoned that acetals might be better
nucleophiles than benzylic ethers for gold-catalyzed carboalkox-
ylation because of the stronger resonance stabilization of
oxocarbenium ions. We also posited that an additional benefit
of the increased electronic stabilization could be a reduction of
the chirality transfer efficiency, which would provide additional
opportunities for enantioinduction. Hydrolysis of the initially
formed enol ether product would provide enantioselective
access to 3-alkoxyindanones and cyclopentenones (Scheme 1c).
The prevalence of these structural motifs in natural products
and bioactive molecules makes them valuable targets for
enantioselective synthesis.6 However, few methods for their
preparation have been reported, and no catalytic enantiose-
lective approaches are available.7 Herein we report the highly
enantioselective gold-catalyzed carboalkoxylation of alkynyl
acetals as a concise and convenient means of accessing diverse
enantioenriched 3-alkoxyindanones and cyclopentenones.
Furthermore, we present evidence for trapping of the vinylgold
intermediate as the enantiodetermining step, in contrast to our
previous work with benzylic ethers.
old(I)-catalyzed carboalkoxylation of alkynes affords a
G
direct and atom-economical synthetic approach to
diversified cyclic enol ethers bearing stereogenic centers at
the β position.1,2 We2a and Rhee2d reported that carboalkox-
ylation occurs with efficient chirality transfer from enantioen-
riched benzylic ethers (Scheme 1a) and N,O-acetals (Scheme
Scheme 1. Ether Nucleophiles in Gold(I)-Catalyzed
Carboalkoxylation
We began our investigation by examining the carboalkox-
ylation of alkyne 1a with cationic gold(I) catalysts bearing
different chiral bisphosphine ligands (Table 1).8 Although these
catalyst systems all gave good yields, only DTBM-MeO-
Biphep(AuCl)2/AgSbF6 induced any significant enantioselec-
tivity (entry 4). To our delight, simply changing the solvent
from CH2Cl2 to CCl4 dramatically improved the ee to 94%
without any loss in yield (entry 5). Other nonpolar solvents
were screened. Among them, toluene gave the best results,
affording the desired indanone 3 in 88% yield with 94% ee
(entry 7). Finally, decreasing the loading of AgSbF6 to 2.5 mol
% further increased both the yield and enantioselectivity (92%
isolated yield and 95% ee, respectively; entry 8).
With these optimized conditions in hand, we next
investigated the scope of the gold(I)-catalyzed enantioselective
carboalkoxylation reaction of alkynes (Table 2). Changing from
a dimethyl acetal to a diethyl acetal produced the
corresponding indanone with slightly lower enantioselectivity
(3a vs 3b). The impact of substituents on the aromatic ring was
also investigated. Substrates with an electron-withdrawing
group (Cl, F), an electron-donating group (MeO), or two
1b), respectively. Despite the intensive development of
homogeneous gold(I)-catalyzed enantioselective reactions,
enantioselective carboalkoxylation of alkynes has posed an
unsolved challenge.3 This could be attributed in part to the low
reactivity of the ether C−O bond, which necessitates the use of
highly electrophilic catalytic systems and precludes many others
developed for enantioselective gold catalysis. In addition, our
group’s previous work pertaining to chirality transfer suggested
that initial desymmetrization of sterically modest ether linkages
might be required.2a,4
Received: July 12, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
a
substituents on the aryl ring all were well-tolerated (3c−i).
While the gold-catalyzed reaction to form 7-substituted
indanone 3j required a prolonged reaction time, excellent
enantioselectivity was still obtained. On the other hand, the
reaction of a naphthalene-derived substrate proceeded
smoothly under the standard reaction conditions (3k).9 We
next explored the reactivities of internal alkynes. Alkynes with
phenyl (R2 = Ph) or alkyl (R2 = iPr) substitution were
Table 1. Optimization of the Reaction Conditions
unreactive. An electron-withdrawing ester substrate (R2
=
CO2Me) afforded a nearly quantitative yield of enol ether
product (3l), but the enantioselectivity was moderate (60%
ee).10
The possibility of generating 4-methoxycyclopentenones by
the gold-catalyzed reaction of simple vinyl actetylenes was also
examined (Table 3). Gratifyingly, the reaction displayed high
b
c
entry
L
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L4
L4
L4
L4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CCl4
75
77
71
74
74
80
88
92
8
2
ab
,
5
Table 3. Substrate Scope of Vinyl Acetylenes
24
94
89
94
95
benzene
toluene
toluene
d
8
a
Reaction conditions: (1) 2.5 mol % gold catalyst, 5 mol % AgSbF2,
0.05 mmol of 1a, 10 mg of 4 Å molecular sieves (MS), 1 mL of
solvent; (2) 2.5 mol % PTSA·H2O, 1 mL of CH2Cl2, 0.1 mL of H2O.
b
c
Isolated yields. Determined by chiral HPLC. Absolute stereo-
chemistries were assigned by analogy to 3k (see the Supporting
d
Information). 2.5 mol % AgSbF6 was used.
ab
,
Table 2. Substrate Scope of Aryl Acetylenes
a
b
For the reaction conditions see Table 2, footnote a. Isolated yields
are shown; ee’s were determined by chiral HPLC.
enantioselectivities for substrates with different ring sizes.
Although the yields for these substrates were slightly lower than
for phenyl acetylenes, the rapid assembly of various bicyclic
cyclopentenones from easily prepared substrates11 greatly
expands the synthetic versatility of the gold-catalyzed reaction.
We envisioned two possible pathways to explain the origin of
the enantioinduction (Scheme 2). In the first possibility,
coordination of the chiral cationic gold(I) complex to the
alkyne moiety would result in desymmetrizing alkoxylation of
the triple bond.12 In analogy to the previously studied chirality
transfer of benzyl ethers,2a the resulting intermediate A bearing
a chiral acetal-derived cation would undergo rearrangement
through chirality-preserving intermediate B-chiral to provide C
Scheme 2. Two Possible Pathways
a
Reaction conditions: (1) 2.5 mol % (R)-DTBM-MeO-Biphep-
(AuCl)2, 2.5 mol % AgSbF6, 0.2 mmol of 1, 50 mg of 4 Å MS, 2
mL of toluene; (2) 2.5 mol % PTSA·H2O, 4 mL of CH2Cl2, 0.4 mL of
b
H2O. Isolated yields are shown; ee’s were determined by chiral
HPLC. Absolute stereochemistries were assigned by analogy to 3k
c
(see the Supporting Information). Ar = 4-bromobenzenesulfonyl; 5.0
d
mol % gold catalyst and 10 mol % AgSbF6 were used. Enol ether
hydrolysis was not performed.
B
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Journal of the American Chemical Society
Communication
and subsequently 2a. In this case, the first step would be the
enantiodetermining step (EDS). On the other hand, it is
possible that oxocarbenium intermediate B is sufficiently long-
lived to relax to an achiral conformation, B′-achiral, that would
undergo enantioselective cyclization to afford C. In this second
possibility, the nucleophilic addition of a vinylgold species to
the oxocarbenium intermediate would be the EDS.5,13−15
To distinguish between these two plausible mechanisms, the
gold-catalyzed reaction of mixed acetal 4a (dr = 1.3:1) was
examined (Scheme 3). We anticipated that the sterically
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge NIH NIGMS (R01 GM073932) for
financial support. W.Z. is grateful to Shanghai Institute of
Organic Chemistry and Zhejiang Medicine for a joint
postdoctoral fellowship. We thank Yi-Ming Wang for helpful
discussions and proofreading of the manuscript.
Scheme 3. Mixed Acetal Study
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Journal of the American Chemical Society
Communication
(10) In some cases, the obtained enol ether product partially
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(11) Vinyl acetylene substrates were prepared from commercially
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́
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diazoesters was reported. See: Pawar, P. K.; Wang, C.-D.; Bhunia, S.;
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D
dx.doi.org/10.1021/ja407150h | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX